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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1354.)
© 2002 American Heart Association, Inc.

Thrombosis

Homocysteine Binds to Human Plasma Fibronectin and Inhibits Its Interaction With Fibrin

Alana K. Majors^*; Shantanu Sengupta^*; Belinda Willard; Michael T. Kinter; Reed E. Pyeritz; Donald W. Jacobsen

From the Department of Cell Biology (A.K.M., S.S., B.W., M.T.K., D.W.J.), Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, and the Division of Medical Genetics (R.E.P.), Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Donald W. Jacobsen, Department of Cell Biology, NC10, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail jacobsd{at}ccf.org

Objective— More than 70% of circulating homocysteine is disulfide-bonded to protein, but little is known about the specific proteins that bind homocysteine and their function as a consequence of homocysteine binding.

Methods and Results— When human plasma was incubated with [³⁵S]L-homocysteine, most of the homocysteine bound to albumin. However, additional homocysteine-binding proteins were detected, and 1 of them comigrated with fibronectin. Treatment with 2-mercaptoethanol removed the bound homocysteine, demonstrating the involvement of disulfide bonding. In contrast, [³⁵S]L-cysteine did not bind to fibronectin. Purified fibronectin bound 5 homocysteine molecules per fibronectin dimer. SDS-PAGE of a limited trypsin digestion of homocysteinylated fibronectin showed that several tryptic fragments contained [³⁵S]homocysteine. Sequence analysis demonstrated that the fragments containing bound homocysteine had localized mainly to the C-terminal region, within and adjacent to the fibrin-binding domain. Homocysteinylation of fibronectin significantly inhibited its capacity to bind fibrin by 62% (P<0.005). In contrast, neither the binding of fibronectin to gelatin nor its capacity to serve as an attachment factor for aortic smooth muscle cells was affected.

Conclusions— These results suggest that homocysteine may alter normal thrombosis and delay or interfere with wound healing by impairing the interaction of fibronectin with fibrin.

Key Words: homocysteine • fibronectin • fibrin • atherosclerosis • thrombosis

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